Al Is
`
`19tb
`1-1D4411PUU0
`—0— (cid:9)
`iltNALS Uk uLL :A4tueiiTiC
`
`9 (cid:9)
`
`OIL
`
`BRITISH MEDICAL ASSOCIATION TAVISTOCK SQUARE LONDON WCIH 9JR
`
`This material wascopied
`at the N Lripl and maybe
`Subjdrt US Copyright Laws
`
`Ex. 1074 - Page 1
`
`

`

`Annals of the Rheumatic Diseases
`
`A journal of clinical rheumatology and connective tissue research
`
`
`This journal was founded by the Empire Rheumatism Council, now the Arthritis and Rheutnatign
`Council for Research in Great Britain and the Commonwealth
`
`Advice to contributors
`Communications This journal exists to publish work on all
`aspects of rheumatology and disorders of connective
`tissue. Laboratory as well as clinical studies are welcome.
`In addition brief communications, for example reports of
`single cases, will be printed if of exceptional interest.
`Papers, which will be accepted on the understanding that
`they have not been and will not be published elsewhere
`and are subject to editorial revision, should he addressed
`to The Editor, Professor H L F Currey, London Hospital
`Medical College, London El 2AD. Each author must sign
`the covering letter as evidence of consent to publication.
`Two copies should he supplied, one a typed top copy.
`Authors requiring acknowledgement of papers submitted
`should enclose a stamped addressed postcard or, if
`overseas, an international reply paid coupon.
`Articles must be typewritten on one side of the paper
`only, in double spacing with ample margins. Only recog-
`nised abbreviations should he used,
`
``Viewpoint' articles are intended to present a personal
`view, in not more than 1500 words, of themes currently
`interesting rheumatologists. Contributions of this kind are
`welcome, but it is suggested that readers wishing to
`submit such articles should first discuss their subject and
`scope with the Editor.
`
`SI units If the work is not reported in SI units, the
`equivalent in SI units must be given in parentheses after
`the units used.
`
`Key words Three to 10 key words or short phrases should
`be provided below the summary. They are to assist
`indexers in cross-indexing the article, and they therefore
`should not include words already in the title. When
`possible the terms used should he from the list of medical
`subject headings in the Index Medics (MESI I).
`References In accordance with the Vancouver agreement
`references, which must he typed double spaced, are cited
`by the numerical system.
`A paper (or book) cited in the text is referred to there by
`a superscript number. In the list of references the papers
`(or books) appear in the numerical order in which they arc
`cited in the text, not in alphabetical order by author's
`names. For convenience in preparing the typescript the
`reference number may be typed between parentheses on
`the line, not superscript. The titles of journals are
`abbreviated in accordance with the style of
`Index Medic:ay.
`In the typescript they should either be abbreviated in that
`style or given in full. Three examples follow:
`I
` Green A B, Brown C D, Grey E F. A new method of
`measuring the blood glucose.
`Ann Rheum Dis 1980; 64:
`27--9.
`2 Green A B, Brown C D.
`London: Silver .Books, 1980.
`3
` Grey E F. Diseases of the pancreas. In: Green A B,
`Brown C D, eds.
`Textbook of Medicine. London: Silver
`Books, 1980: 349-62.
`
`Textbook of Medicine.
`
`References will not be checked in the editorial office.
`Responsibility for their accuracy and completeness lies
`with the author.
`
`Illustrations must be marked on the back with the author's
`name, numbered, in the same order as they arc cited in the
`text, and have the top indicated. All lettering and syinhols
`on their face must be inserted by the author and he large
`enough for reproduction on the page. Radiographs must
`
`double
`be submitted as prints. Legends must be typed in
`spacing on a separate sheet and include for photomicro-
`graphs the stain and magnification.
`
`Tables Each table should be on a separate sheet, have a
`heading, and contain no vertical rules.
`
`Proof's Contributors will receive °NE proof, and should,
`read it carefully for printers' errors. Alterations to the
`original text should be kept to a minimum and may be
`charged to the author.
`
`Reprints 25 reprints will be supplied free
`Additional reprints may be ordered from the Publish
`Manager when the proofs are returned.
`
`
`of charge.
`ing
`
`Notice to subscribers
`Annuls of die Rheumatic Diseases is published monthlY.,111,,e)
`£94.r
`annual subscription rates are 1:80410 inland and
`sent to the
`overseas (including the USA). Order should be
`iroil?laiii(e)ir(itrwiti(c tDolse,usi,gt.
`Subscrilni,oil l st: . liMiiiviitii l
`
`u ar e ,
`s calls of th
`igsetro,ck nA
`n
`BMA
` Sc
`Orders call ii',, be placed wi t h any leading subscription agcn
`c
`or hooksch.1 . i I iir the convenience of readers in the USA
`'lily' .„ with or without payment,, may also 5
`subscription i
`50 ..'
`sent to: BRITISH MEDICAL JOURNAL, Box
`Kennebunkport, Maine (H(46, USA. All inquiries, howeveh
`m ust lie addressed to the publisher in London.)
`
`All inquiries regarding air mail rates and single copies.
`!Ii4•ii(ly published should also he addressed to the pub'
`11.1iii• in London.
`
`Notice to advertisers
`
`I•••
`
`tii ilp• Advertisement Manager, Antlalc
`
`London W(; III 9J R.
`
`by the
`
`Annals of the Rheumatic Diseases.
`This publication is copyright under the Berrie C°rIiiveringti°1.51)
`under
`be
`ands the International Copyright Convention. All
`permitted (cid:9)
`‘res, (cid:9)
`Apart from any relaxations
`to
`
`tonal cyright laws, no part of this publication 11117d narved.
`it.ion of
`reproduced stored in a retrieval system. or traosT
`any form or by any means without the prior perouss'uired
`a
`they
`to copyright owners. Permission is not, however' require
` on condition .00 of
`fullcopy abstracts of papers or of articles
`copY!orio is
`he reference to the source is shown. Multiple
`contents of the publication without Perillissj
`t
`always illegal.
`
`This m atsria I W25{13piali
`at the NLM and maybe
`Subject LIS Copyright Laws
`
`Ex. 1074 - Page 2
`
`(cid:9)
`

`

`Annals of the Rheumatic Diseases (cid:9)
`
`September 1986 Vol. 45 No. 9
`
`Contents
`
`A three year follow up of patients allocated to placebo, or oral or injectable gold therapy for
`rheumatoid arthritis H A CAPELL, D LEWIS, AND 1 CAREY (cid:9)
`Binding of sodium aurothiomalate to human serum albumin in vitro at physiological conditions
`SUSANNE MOLLER PEDERSEN (cid:9)
`Pharmacodynamic effect of dipyridamole on thallium-201 myocardial perfusion in progressive
`systemic sclerosis with diffuse scleroderma ANDRE KAIIAN, JEAN Y DEVAUX, BERNARD AMOR.
`CHARLES J MENKES, SIMON WEBER, JEAN M FOULT, ALAIN VENOT', ERAKOIS GUERIN, MICHEL DEGEORGES,
`
`AND JEAN C ROUCAYROL (cid:9)
`Cyclosporin treatment for rheumatoid arthritis: a placebo controlled, double blind, multicentre study
`A W AM VAN RIJTHOVEN, B A C DIJKMANS, H S GOEI THE, 1 HERMANS, Z I. M B MONTNOR-BECKERS,
`
`P C J JACOBS, AND A CATS (cid:9)
`Cyclosporin A (CyA) in primary Sjogren's syndrome: a double blind study A A DROSOS,
`F N SKOPOULI, J S COSTOPOULOS, C S PAPADIMITRIOU, ANI) II M MOUTSOPOULOS (cid:9)
`Pulmonary involvement in ankylosing spondylitis NILS FELTELIUS, HANS HEDENSTRoM,
`GUNNAR HILLERDAL, AND ROGER HALLGREN (cid:9)
`Nailfold capillary microscopy in connective tissue disease: a quantitative morphological analysis
`F LEFFORD AND 1 C W EDWARDS (cid:9)
`Osteogenesis imperfecta: a x ray fibre diffraction study 1 P BRADSHAW ANI) A MILLER (cid:9)
`Bone metabolism during methylprednisolone pulse therapy in rheumatoid arthritis J W 1 13111.SMA,
`S A DUURSMA, AND 0 HUBER-BRUNING (cid:9)
`Neutropenia in patients with inflammatory arthritis treated with sulphasalazine M PARR,
`D P M SYMMONS, D R BLAKE, ANI) P A BACON (cid:9)
`Significance of connective tissue proliferation in the breakdown of cartilage: a novel in vivo model
`F B DE BRITO, A R MOORE, S ADIIYA, A Y AL-DUAIJ, AND I) A WILLOUGHBY (cid:9)
`Pulmonary hypertension in hydralazine induced systemic lupus erythematosus: association with C'4
`null allele RONALD A ASHERSON, ALASTAIR 6 BENBOW, CHRISTOPHER 1 SPURS, N JACKSON, AND
`GRAHAM R V HUGHES (cid:9)
`Idiopathic peripheral enthesopathy without spondylarthritis M NISIIIKAI, M SUGIMOTO, A sATo, AND
`H TAKEUCHI (cid:9)
`Unusual radiographic features in a female patient with ankylosing spondylitis TIMOTHY 1
`CUNNINGHAM, PETER M CUMBER, GORDON EVISON, ANI) PETER J MADDISON (cid:9)
`Spontaneous pneumomediastinum in adult dermatomyositis Joim i) BRADLEY (cid:9)
`Monarticular rheumatoid-like arthritis of seven years' duration following fracture of the radial head
`JACQUELINE CURREY, I. II K THERKILDSEN, AND E G I. BYWATERS (cid:9)
`Conference report (cid:9)
`Correspondence (cid:9)
`Note (cid:9)
`
`Page
`
`705
`
`712
`
`718
`
`726
`
`732
`
`736
`
`741
`750
`
`757
`
`761
`
`765
`
`771
`
`774
`
`776
`780
`
`783
`786
`788
`792
`
`ASTMS CODEN: ARDIAO 45 (9) 705-792 (1986) (cid:9)
`
`ISSN 0003-4967
`
`British Medical Association Tavistock Square London WC 11-1 9JR
`
`Published by British Medical Association, Tavistock Square, London WCIII 9JR. and
`printed in England by The Devonshire Press Ltd., Torquay
`
`This material was copied
`atthe NBA and may be
`Subject US Copyright Laws
`
`2045
`
`Ex. 1074 - Page 3
`
`(cid:9)
`

`

`Annals of the Rheumatic Diseases 1986, 45, 726-731
`
`Cyclosporin treatment for rheumatoid arthritis: a
`placebo controlled, double blind, multicentre study
`
`J AWA M VAN RLITHOVEN,' B A C DIJKMANS,2 (cid:9)
`HERMANS,4 Z L M B MONTNOR-BECKERS,' P C
`A CATS2
`
`'University Hospital, Leiden;
`, Leiden, The
`
`From the 'Department of Rheumatology, Deaconess Hospital, Eindhoven; the
`the ''De Wever Hospital, Heerlen; and the 4 Department of Medical Statistics, University
`Netherlands
`
`s GOEI TVE,3
`
`J JACOBS,- AND
`
`SUMMARY The efficacy and safety of cyclosporin for patients with rheumatoid arthritis (RA)
`The initial
`were assessed in a six month double blind, placebo controlled, multicentre study.
`dosage of the drug was 10 mg/kg daily for two months. There were many discontinuations in both
`the cyclosporin group (eight out of 17) and the placebo group (six out of 19). Of the patients who
`completed the six months of therapy, those who had received cyclosporin showed a significant
`improvement in the number of swollen joints, the Ritchie articular index, and pain at active
`movement and at rest, compared not only with their condition at the start of the study, but also
`with the end results of the placebo group. Major adverse reactions to the drug were
`gastrointestinal disturbances and nephrotoxicity, which were probably due to the relatively high
`dosages of cyclosporin given in combination with non-steroidal anti-inflammatory drugs.
`
`The treatment of patients with rheumatoid arthritis
`(RA) is a challenging problem for rheumatologists.
`Several clinical studies have shown that antima-
`lanais, gold salts, n-penicillamine, and some cyto-
`static agents have disease activity modifying
`properties," but the response to treatment with
`these drugs is variable and a certain proportion of
`the RA patients do not benefit. These unresponsive
`patients are considered to have refractory RA, an
`intriguing hut daunting problem to the practising
`clinician.
`Cyclosporin is a fungal peptide with unique
`immunosuppressive properties, inhibiting activation
`of both B and T lymphocytes and certain mac-
`rophage functions.' In the clinical situation the
`activity of cyclosporin is highest when the drug is
`administered during the inductive phase of an
`immune response (sensitisation), i.e., at the time of
`organ transplantation. In animal models of autoim-
`mune diseases, however, i.e., after sensitisation,
`cyclosporin also suppresses the effector phase.'
`Although its action has been reported to be rever-
`
`Accepted for publication 19 March 1986.
`Correspondence to Professor A Cats, Department of Rheuma-
`tology, University Hospital, Building 1, C2O, PO Box 9600, 2300
`RC Leiden, The Netherlands.
`
`Bible, studies on experimental arthritis in rats
`suggest a long lasting effect of this drug!'
`These findings and the favourable results of
`cyclosporin treatment of other autoimmune diseases
`in man9 19 led us to perform a double blind, placebo
`controlled, multicentre study to evaluate the effi-
`
`cacy and safety of this drug in patients wit h
`refractory RA.
`
`Patients and methods
`
`Patients with active and erosive definite or classical
`RA, according to the American Rheumatism As-
`sociation criteria, and who had previously been
`treated with antimalarials and gold salts or D-
`penicillamine were included in the study. Further
`criteria for entry were anatomical and functional
`stage 11 or III" and termination of corticosteroid
`therapy at least six months before the start of the
`study. Patients who had a history of cancer, a
`serious concomitant illness, abnormal liver or renal
`function, or both, extra-articular manifestations of
`RA other than nodules, or who had undergone joint
`surgery within the preceding three months were
`excluded. Other exclusion criteria were: a white cell
`count of less than 3000/mm3 (3x 109/1), a platelet
`
`726
`
`This material was copied
`at the NLM arid may be
`Subject USCopyright Laws
`
`Ex. 1074 - Page 4
`
`

`

`count below 100 000/me (100x lel), and con-
`comitant therapy with potentially nephrotoxic drugs
`except non-steroidal anti-inflammatory agents.
`After their informed consent had been obtained
`the patients were allocated randomly to either the
`oral cyclosporin or the placebo group, each centre
`having a separate list of the random allocations. The
`itlitial cyclosporin dosage was 10 mg/kg once a day
`gi ven a t noon for two months. If there was a
`satisfactory response the dosage was reduced to 7.5
`rtig/kg once a day (months 3 and 4) and then to 5
`mg/kg once a day (months 5 and 6). The dosage
`was adjusted according to clinical response and side
`effects. Furthermore, patients were monitored on
`the basis of trough blood levels of cyclosporin.
`blood samples for the measurement of these con-
`centrations were drawn into heparinised tubes and
`stored at 4°C for at most one week before the
`Stored
`levels were determined in whole blood
`by a radioimmunoassay' performed with the kit
`supplied by Sandoz. It the trough blood level of
`cyclosporin exceeded 1000 ng/m1 the dosage was
`adjusted, and the same volume reduction was made
`in the paired patient in the placebo group. In both
`groups administration was stopped after six months.
`Non-steroidal anti-inflammatory drugs (NSAIDs)
`were prescribed according to individual need. In
`each centre one rheumatologist, who was not aware
`of side effects or safety parameters, assessed the
`joints of each of the patients of that centre monthly.
`The parameters of efficacy determined monthly
`were as follows: the duration of morning stiffness,
`the number of swollen joints, the Ritchie index, pain
`at active movement and at rest, and grip strength
`Measured with a vigorimeter. Radiographs of hands,
`wrists, and feet were made at entry and after six
`months. Radiological abnormalities of the metacar-
`pophalangeal and metatarsophalangeal joints and
`the proximal interphalangeal joints of hands and
`feet were graded from 0 to 4 (grade 0: no abnormali-
`ties; grade I: dubious erosions; grade 2: definite but
`mild erosions or narrowing of the joint space; grade
`3: more destructive changes; and grade 4: severe
`erosions or ankylosis"), and the sum of these
`abnormalities was called the radiological score.
`After one week and six months of cyclosporin
`therapy a global assessment of efficacy was made by
`the patient and the investigator, both of whom also
`made an overall assessment of efficacy at the end of
`the study (grades: grade 0: no effect; grade 1:
`slight improvement; grade 2: moderate improve-
`ment; grade 3: good improvement; grade 4: excel-
`lent improvement).
`Safety and tolerability were assessed by physical
`examination (body weight, blood pressure, and
`pulse rate) and laboratory tests (cyclosporin blood
`
`Cyclosporin treatment for rheumatoid arthritis 727
`
`levels, serum levels of creatinine and potassium,
`liver enzymes); these parameters were evaluated by
`a second doctor in each centre who was not involved
`in the assessment of efficacy parameters.
`
`Table I characteristics of the 36 rheumatoid arthritis
`patients after random allocation to the cyclosporin and
`placebo groups
`
`Parameter (cid:9)
`
`Sex (cid:9)
`Age (years)
`Duration of illness
`(years)
`Functional stage (cid:9)
`
`Anatomical stage (cid:9)
`
`*mean (SD; range).
`
`Cyclosporin group (cid:9)
`(n=17) (cid:9)
`
`Placebo group
`(n=19)
`
`13 F/4 M
`54.5 (12.9; 24-69)*
`
`15 F/4 M
`55.3 (9.7; 37-68)
`
`11.8 (6.2)
`II (n=12)
`III (n=5)
`II (n=6)
`III (n=11)
`
`14-5 (11.3)
`II (n=10)
`111 (n=9)
`II (n=8)
`III (n=11)
`
`Table 2 Kind and frequency of side effects in both groups
`of rheumatoid arthritis patients in the present study
`
`Side effects
`
`Cyclosporin (cid:9)
`group (cid:9)
`(n=17) (cid:9)
`
`Placebo
`group
`(n=19)
`
`Gastric pain (cid:9)
`Nausea
`Vomiting
`Rise of serum creatinine level
`Hyperkalacmia
`Urine retention
`Hirsutism
`Tremor
`Gingival hyperplasia
`Hyperaesthesia
`Headache
`
`5 (cid:9)
`9 (cid:9)
`3 (cid:9)
`13 (cid:9)
`1 (cid:9)
`1 (cid:9)
`3
`2
`3
`5
`0 (cid:9)
`
`2
`3
`0
`5
`0
`0
`0
`0
`0
`
`4
`
`Table 3 Time of and reason Jr discontinuation of
`cyclosporin or placebo administration during the present
`study
`
`Group
`
`Reason
`
`Time (weeks)
`
`Cyclosporin Ilyperkalaemia
`Non-compliance
`Gastrointestinal intolerance,
`raised serum creatinine level
`Gastrointestinal intolerance
`Gastrointestinal intolerance
`Gastrointestinal intolerance
`No effect
`Rise of serum creatinine level
`
`Placebo
`
`No effect
`No effect
`No effect
`No effect
`No effect
`Duodenal ulcer
`
`6
`6
`
`6
`6
`8
`S
`12
`19
`
`2
`8
`8
`10
`16
`20
`
`This material wascopied
`at the NLM and may be
`Subject USCopyright Laws
`
`Ex. 1074 - Page 5
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`728 van Rijth oven, Dijk mans, Goei The, Hermann,
`
`Pain on active movement
`(score range: 0-3)
`
`Pain at rest
`(score range: 0-3)
`
`Erythrocyte sedimentation rate
`(ESR) (mm/lst h)
`
`Radiological score
`
`2.4
`2.4
`
`1-5
`1.3
`
`50
`65
`
`96
`105
`
`(0.6)
`(0-71
`
`(n=17)
`(n=91
`
`(1.2)
`0.3)
`
`(n=1-..)
`(n=91
`
`(40)
`(42)
`
`(38)
`(33)
`
`(n=16)
`(n=8)
`
`(n=1-)
`(n= 91
`
`1-6
`p=0-01
`
`0.6
`p=0.01
`
`(1.0)
`
`(n=9)
`
`(0.9)
`
`(n=9)
`
`50
`NS
`
`115
`NS
`
`(24)
`
`(n=9)
`
`(401
`
`(n=9)
`
`2-2
`2-0
`
`1-!
`0.0
`
`58.
`44
`
`667
`
`(0-7) (n=19)
`(0-6) (n=13)
`
`(0-9) (n=19)
`(0.8) (n=13)
`
`(n=19)
`(31) (cid:9)
`(23) (n=13)
`
`(t44.31 11 (cid:9)
`
`(Jin=_1193)
`
`2-2
`NS
`
`1.1
`NS
`
`(1.0)
`
`(n=13)
`
`0-07
`
`(25)
`58 (cid:9)
`1)=0.05
`
`(n=13)
`
`NS
`
`(40)
`
`(n=131
`
`NS
`
`102
`NS
`
`• For comparison ot the two groups with respect to their ditterenees between the start and end ot the stud).
`/Mean (SE)).
`;Number ot patients.
`§Number ot patients assessed up to six months.
`hDifterence within the groups between start and end ot the stud)
`
`Table 4 Clinical and laboratory parameters of efficacy of treatment in both groups of rheumatoid arthritis patients in the present study
`
`Parameter (cid:9)
`
`Cyclosporin group (cid:9)
`
`At time 0 (cid:9)
`
`At six months
`
`Morning stiffness (min)
`
`Number of swollen joints
`
`Ritchie index
`
`69
`58
`
`10.5
`10-3
`
`22-2
`73-6
`
`(43)t
`(32)
`
`(n=17)::-t
`(n=9)§
`
`(2-8)
`(2.5)
`
`(n=1.7)
`(n=9)
`
`(8.11
`(8.1)
`
`(n=17)
`(n=9)
`
`56
`NS
`
`3.8
`p=0.01
`
`11.1
`p=0.01
`
`(78)
`
`(n=8)
`
`(4-8)
`
`(n=9)
`
`(5.8)
`
`(n=9)
`
`Placebo group
`
`At time 0
`
`68
`52
`
`9.1
`8.3
`
`(n=18)
`(56) (cid:9)
`(43) (n=13)
`
`(3-3) (n=19)
`(3-0) (n=13)
`
`22-9
`'1-3
`
`(8.0) (n=19)
`(6.9) (n=13)
`
`p Value*
`
`At six months
`
`47
`NS
`
`6.1
`NS
`
`18-3
`NS
`
`(43)
`
`(n=13)
`
`NS
`
`(2-7)
`
`(n=13)
`
`002
`
`(6.5)
`
`(n=13)
`
`0.03
`
`(0.7)
`
`(n=13)
`
`0-01
`
`Ex. 1074 - Page 6
`
`(cid:9)
`

`

`cyclosporin treatment for rheumatoid arthritis 729
`
`The Wilcoxon two sample test was used for
`statistical analysis of the data for comparison of the
`two groups, and the signed rank test was applied for
`analysis within the groups.
`
`}Jesuits
`
`Thirty six patients (28 women and eight men, mean
`age 54.9 years, SD 11.2, range 24-69 years) were
`admitted to the study. The cyclosporin group
`comprised 17 patients and the placebo group 19; the
`demographic characteristics of the patients, which
`ale shown in Table 1, indicate an equal distribution
`over the groups. During the trial the frequency of
`side effects was considerable in both groups (Table
`2). The cyclosporin group showed a highly signifi-
`cant (p<0.005) rise of the serum creatinine level
`relative to the pretreatment values, the mean values
`for the group being 98.7 (SD 31.4) and 72.6 (SD
`18.2) jtmo1/1, respectively; in two patients the rise of
`tIle serum creatinine level was judged unacceptable
`for continuation of cyclosporin administration
`(Table 3). Other reasons for withdrawing the drug in
`the cyclosporin group were gastrointestinal intoler-
`ance in four patients and absence of effect, hyperka-
`laemia, and lack of compliance, each in one patient
`(Table 3). In the placebo group administration was
`stopped in five patients because of lack of effect and
`in one patient who developed a duodenal ulcer
`(Table 3).
`
`The findings concerning clinical, laboratory, and
`radiological efficacy parameters for the two groups
`are given in Table 4. Statistical analysis disclosed
`that at the start of the study the groups were
`comparable for each of the efficacy parameters.
`Further analysis was restricted to the patients who
`completed the six months of therapy. Comparison of
`the changes in both groups during the study showed
`significant improvement for the cyclosporin group
`with respect to the number of swollen joints, the
`Ritchie index, and pain on active movement, and
`pain at rest showed borderline significance (Table
`4). The changes in efficacy parameters within the
`groups over the same period are also shown in Table
`4.
`As these data indicate, in the placebo group no
`improvement occurred in any of the parameters and
`the ESR was significantly higher at six months than
`at the start of the study. The cyclosporin group
`showed a non-significant decrease of the sedimen-
`tation rate (from 65 mm to 50 mm after one hour),
`significant improvement in the number of swollen
`joints, Ritchie index, and pain at both active
`movement and rest at six months and also less
`radiological progression of joint destruction, but this
`last was not significant relative to the placebo group.
`The other parameters of efficacy and safety are
`given in Table 5. At the end of the study period the
`values for grip strength did not differ either between
`or within the groups. The mean score for global
`
`Table 5 Other efficacy and safety parameters assessed in patients with rheumatoid arthritis in the present study
`
`Parameter
`
`Cyclosporin group
`
`Placebo group
`
`p Value*
`
`Grip strength ( Kpa )
`Left hand
`Right hand
`Global efficacy
`(score range: OA)
`Patient
`Investigator
`Overall efficacy
`(score range: 0-4)
`Patient
`Investigator
`I laemoglobin (mmo1/1)
`Alkaline phosphatase (U/I)
`S-Alaninc aminotransferase
`(ALAT) (U/I)
`Potassium (mmo1/1)
`
`At time 0
`
`At six months
`(n = 9)
`
`At time 0
`
`At six months
`
`(n=13)
`
`11.3
`12.9
`
`(9.2)t
`(11.2)
`
`13.7
`15.0
`
`(12.4) NSt
`(14.3) NS
`
`15.9
`17.5
`
`(10.0)
`(10.9)
`
`15.1
`17.2
`
`(9.4) NS
`(12.7) NS
`
`NS
`NS
`
`0.6
`0.3
`
`(1.0)§
`(0.7)§
`
`I.8
`1.9
`
`(1.3) 0.07
`(1.3) 0.02
`
`0.4
`0.3
`
`(0.7)
`(0.6)
`
`0.6
`0.5
`
`(1.0) NS
`(0.7) NS
`
`NS
`0.01
`
`7.9
`102
`
`(1.0)
`(47)
`
`10
`4.4
`
`(5.1)
`(0.4)
`
`2.5
`2.8
`7.7
`96
`
`(1.1)
`(0.9)
`(0.9) NS
`(31) NS
`
`7.9
`86
`
`(1.0)
`(21)
`
`9.4
`4.6
`
`(6.4) NS
`((l•5) NS
`
`9.6
`4.5
`
`(4.2)
`(0.3)
`
`1.1
`0.7
`7.6
`91
`
`11.9
`4.3
`
`(1.3)
`(1.0)
`(1.1) NS
`(27) NS
`
`(16.1) NS
`(0.2) NS
`
`0.0711
`o•oli
`NS
`NS
`
`NS
`NS
`
`*For comparison of the two groups with respect to their differences between the start and end of the study.
`tMean (SD).
`#Difference within group between start and end of the study.
`§Measured after one week of treatment.
`iDifference between the two groups at six months.
`
`This material was copied
`at the NLM and may be
`Subject US Copyright Laws
`
`Ex. 1074 - Page 7
`
`

`

`730 van Rijthoven, Dtjkmans, Goei The, Hennans, Montnor-Beckers, Jacobs, Cats
`starting dose), which are reflected in the relatively
`efficacy was significantly higher for the cyclosporin
`high mean trough blood cyclosporin concentrations.
`group than for the placebo group at six months, as
`At present it is advised that blood levels higher than
`assessed by the investigator. Moreover, the score for
`600-800 µg/ml should he avoided for cyclosporin
`the cyclosporin group as assessed by the investigator
`treated patients with an autoimmune disease. I 7
`was significantly higher at the end of the study than
`Moreover, the concomitant treatment with NSAIDs
`at the beginning, but was the same at both time
`might have led to gastrointestinal disturbances and
`points for the placebo group. At the end of the study
`nephrotoxicity. Besides nephrotoxicity due t o
`the score for overall efficacy as assessed by the
`NSAIDs,1 ' the kidney in rheumatoid arthritis
`investigator was significantly higher for the cyclo-
`patients can be directly involved. owing to the
`sporin than the placebo group.
`disease. l `' An increased incidence of disturbances of
`Mean values for haemoglobin, alkaline phospha-
`the upper gastrointestinal tract in rheumatoid arthri-
`tase, ALAT, and potassium did not change during
`tis patients has been reported, but it is not Clear
`the study either between or within the groups.
`whether this is related to the drug. treatment or
`The mean value for the cyclosporin blood levels of
`represents a systemic manifestation of the disease.'`
`all 17 patients treated with cyclosporin was 675 (SD
`In summary, cyclosporin proved to be more
`223) ng/ml.
`effective than placebo during a six month treatment
`period in patients with rheumatoid athritis refrac-
`tory to more conventional drugs. The observed
`adverse affects may have been dose related and
`enhanced by concomitant therapy with NSA I Ds.
`Thus cyclosporin seems to be an effective disease
`modifying drug in rheumatoid arthritis, provided it
`is given in a daily dose not exceeding 5 mg/kg and is
`well monitored, with blood trough levels not ex-
`ceeding 500 ng/ml. Moreover, to avoid nephrotox-
`icity we recommend the omission of concomitant
`administration of NSA1Ds with the possible excep_
`tion of sulindac, which is claimed to give less renal
`dysfunction.21
`
`Discussion
`
`The main conclusion drawn from the results of this
`placebo controlled, double blind study is that
`cyclosporin improves clinically manifest symptoms,
`i.e., the number of swollen joints, Ritchie articular
`index, and pain at active movement and at rest, in
`patients suffering from active rheumatoid arthritis.
`No significant improvement in morning stiffness or
`laboratory parameters was found, and the placebo
`group showed a significant rise of the ESR. This six
`month study did not yield any evidence that cyclo-
`sporin can retard radiographic signs of deterioration.
`Reduction of radiographic progression of joint
`destruction, however, is by no means an effect of all
`'remittive agents' or disease modifying drugs, and
`the only available evidence that both gold and
`cyclophosphamide can retard radiographic de-
`terioration is circumstantial." Cyclosporin may
`even retain its activity after the inductive phase of
`the immune response in the clinical situation since it
`is conceivable that in rheumatoid arthritis sensitis-
`ation has already occurred.
`The number of withdrawals from the study was
`high in both groups, but the total of five in the
`placebo group because of inefficacy suggests that the
`basis chosen for the selection of patients was good.
`The improvement of symptoms in the patients with
`active rheumatoid arthritis treated with relatively
`high dosages of cyclosporin should, however, be
`considered in the light of the adverse reactions, i.e.,
`gastrointestinal disturbances and raised serum
`creatinine levels. This rise in serum creatinine
`proved partially irreversible (unpublished data),
`which is not the case for cyclosporin nephrotoxicity
`in renal allograft recipients. I5 (cid:9)
`It seems probable
`that the gastrointestinal and nephrotoxic reactions in
`our patients can be at least partially ascribed to the
`relatively high dosages of cyclosporin (10 mg/kg as
`
`Cyclo .por in was kindly provided by'Saint./ It V. Uden. .1.11c
`No bet land., The blood concentration., III (cid:9)
`ant were deter-
`nmicd by Dr A 1 Moolcnaar (Leiden. The Nether lands) and Dr A
`(Heerlen. The Netherlands). The authors arc greatly
`indebted to Anita Posing:I for typing the manuscript.
`
`References
`
`I (cid:9)
`
`I I% droxychloroquine %W(ite
`I (cid:9)
`I (cid:9)
`,, (cid:9)
`II,InnluaI I (cid:9)
`I; I> (cid:9)
`III 11, ,I11,111 nl !IP:unhook! arthritis. Arthririv
`(M1,111'11)1)
`Rheum Iw, (cid:9) 5: 3n' I !
`I W IIlul1: o, I. I)unc;ut II. Sharp J (cid:9)
`Ensign I)
`in the treatment 01 rheumatoid
`51,•1 1, 1111 V; (cid:9)
`( .1, 1 (cid:9)
`(HIM, - blind .study. Ann Intern 'Vied 1974; 80: 21-6.
`at thrill (cid:9)
`Itci iv II. I (cid:9)
`R, Durance (' (i, Barnes (' G. Berger 1
`tat compartio, aiathioprine and penicillamine in treatment of
`rheumatoid artlititt,. Ann Rheum Dia 1976; 35: 542 3,
`4 Weinblatt M L, Colblyn 1 S, Fox D A, et al. Efficacy of
`low-dose methotrexate in rheumatoid arthritis. N Engl 1 Med
`1985; 312: 818-22.
`5 Klippel J /1, Decker.' C. Methotrexate in rheumatoid arthritis.
`N Engl.! Med 1985; 312: 853-4.
`6 Hess A 1), Tutschka P 1. Pu Z. Santos G W. Effect of
`cyclosporin A on human lymphocyte responses in vitro. IV.
`Production of T cell stimulatory growth factors and develop-
`ment of responsiveness to these growth factors in CyA-treated
`primary MLR cultures. 1 lmmunol 1982; 128: 360-7.
`7 Borel J F. Cyclosporin A. Present experimental status. Trans-
`plant Proc 1981; 13: 344-8.
`8 Henderson B, Staines N A. Burrai 1. Cox 1 11. The anti-arthritic
`and imtnunosuppressive effects of cyclosporine on arthritis
`
`This material was copied
`atthe NMI and may be
`Subject US Copyright Laws
`
`Ex. 1074 - Page 8
`
`

`

`Cyclosporin treatment for rheumatoid arthritis 731
`
`induced in the rat by type II collagen. (lin Exp Immunol 1984;
`57: 51-6.
`9 Nussenblatt R B. Palestine A 0, Chan C C, Mochizuki M,
`Yancey K. Effectiveness of cyclosporine therapy for Beheet's
`disease. Arthritis Rheum 1985; 28: 671-9.
`10 Stiller C R. Dupre 1, Gent N4, et al. Effects of cyclosporin
`immunosuppression in insulin-dependent diabetes mellitus of
`recent onset. Science 1984; 223: 1362-7.
`I 1 Steinbrocker 0, Traeger C lI. Batterman R C. Therapeutic
`criteria in rheumatoid arthritis. JA MA 1949; 140: 659-62.
`12 Donaisch P, Abisch E, Homberger N4, 'Haber 12, Trapp M,
`Voges R. A radioimmunoassay to measure cyclosporin A in
`plasma and serum samples. J Immunoassay 1981 ; 2: 19-32.
`11 Kellgren .1 II, ed. lite epidemiology of chronic rheumatism.
`Oxford: Blackwell Scientific, 1963. (Atlas of standard radio-
`graphs of arthritis; Vol 2).
`14 lannuzzi L, Dawson N, Zein N, Kushner I. Does drug therapy
`slow radiographic deterioration in rheumatoid arthritis? N
`Engl J Med 1983; 309: 1023-K.
`IS Chapman J R, Griffiths D, I larding N 0 I„ Morris P J.
`Reversibility of cyclosporin nephrotoxicity after three months'
`treatment. Lance/ 1985;i: 128-9.
`
`16 Henny F C, Kleinbloesem C II, Moolenaar A J, Paul L C,
`Breimer D D, Van Es L A. Pharmacokinetics and nephrotoxic-
`ity of cyclosporin A in renal transplant recipients. Transplan-
`tation (in press).
`17 Von Graffenried B, I larrison W B. Cyclosporin in autoimmune
`diseases—side effects (with emphasis on renal dysfunction) and
`recommendations for use. In: Schindler R, ed. cyclosporin in
`autouninune diseases. Berlin: Springer, 1985, 59-73.
`18 Kimberly R I', Bowden R E, Keiser H R, Plotz P H. Reduction
`of renal function by newer anti-inflammatory drugs. Ant J Med
`1978; 64: 804-7.
`19 Breedveld F C, Valentijn R M, Westedt M-L, Weening J J.
`Rapidly progressive glomerulonephritis with glomerular cres-
`cent formation in rheumatoid arthritis. Clin Rheumatol 1985; 4:
`353-9.
`20 Sun D C, Roth S II, Mitchell C S, England D W. Upper
`gastrointestinal disease in rheumatoid arthritis. Am J Dig Dix
`1974; 19: 405-10.
`21 Ciabattoni 0, Cinotti 0 A, Peirucci